Design paperDesign and Baseline Characteristics for the Aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy (ACTION II)
Introduction
The chronic hyperglycemia of type 2 diabetes mellitus can lead to long-term microvascular and macrovascular complications, including neuropathy, retinopathy, nephropathy, and accelerated atherosclerosis 1, 2. Tissue damage may result from excessive chemical interaction between glucose and proteins, resulting in the formation of advanced glycosylation endproducts (AGEs) 3, 4. AGEs arise from the nonenzymatic reaction of carbonyl groups of glucose with amino groups of structural proteins, such as basement membrane collagen. With time, early glycated products (Amadori products) undergo rearrangement and dehydration to form stable protein-bound adducts (AGEs) that can crosslink proteins. AGE-mediated formation of rigid cross-links with matrix proteins and trapping of soluble proteins and lipoproteins in vascular walls is thought to play an important role in the development of diabetic complications [5].
Diabetic patients have markedly higher serum AGE levels than nondiabetics, and AGE levels parallel the severity of diabetic nephropathy [6]. Glycated proteins can continue trapping and cross-linking proteins even in the presence of normoglycemia. Therefore, normalization of glucose in diabetes mellitus may not completely prevent the progression of complications.
Aminoguanidine is a nucleophilic hydrazine derivative that binds irreversibly to reactive intermediates of early glycated products, particularly 3-deoxyglucosone, and prevents AGE formation and AGE-induced protein cross-linking [7]. Aminoguanidine reduces glomerular basement membrane fluorescence, IgG trapping, and albuminuria and slows mesangial matrix expansion in the streptozotocin-induced diabetic rat (at oral dosages of 50 mg/kg/d and higher) 8, 9, 10, 11, 12, 13. The aim of the “Aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy” (ACTION II) is to evaluate the efficacy and safety of two dose levels of aminoguanidine in preventing or slowing the progression of established diabetic nephropathy in patients with type 2 diabetes mellitus. The primary objective is to evaluate the effect of aminoguanidine on the time to doubling of serum creatinine concentration. The secondary objectives are to evaluate the effects of aminoguanidine on time to all-cause mortality, time to cardiovascular morbidity and mortality, time to end-stage renal disease (ESRD), rate of change in glomerular filtration rate by iothalamate clearance, Cockcroft & Gault (C&G) calculation and creatinine clearance in 24-hour urine, rate of change in serum creatinine concentration, change in 24-hour urine protein excretion (versus baseline), change in serum and urine AGE concentration (versus baseline), quality-of-life scores, and changes in diabetic retinopathy. The study will also allow estimation of the relationship between plasma aminoguanidine concentrations and the primary and secondary efficacy endpoints and adverse events. This report describes the design of ACTION II and presents selected baseline demographic and clinical characteristics of the randomized participants.
Section snippets
Population
The target study population consists of patients 30 to 70 years of age with type 2 diabetes mellitus and proteinuria at least 500 mg/d in the presence of either diabetic retinopathy or evidence, from renal biopsy, of diabetic nephropathy. Initial C&G-calculated creatinine clearance was equal to or greater than 40 mL/min with serum creatinine concentration at least 1.0 mg/dL in women and 1.2 mg/dL in men. Patients had systolic blood pressures ⩽180 mm Hg and diastolic blood pressures ⩽120 mm Hg
Baseline characteristics
ACTION II randomized 599 patients. Seventy-two percent of these patients were male, 68% were white, 16% were black, and 16% were Asian American or Native American. Seventy-six percent were receiving concomitant ACE inhibitors, 43% were receiving lipid-lowering medications, and 13% are current smokers. The mean (standard deviation) age of patients was 58 (7.7) years and duration of diabetes was 16.5 (7.5) years. Table 4 lists the clinical characteristics of randomized patients and Table 5 their
Summary
ACTION II will determine whether aminoguanidine, an inhibitor of AGE-mediated protein cross-linking, will slow the progression of established type 2 diabetic nephropathy. Additionally, the trial will gather important information regarding the natural history and effect of aminoguanidine on the complications of type 2 diabetes mellitus and its associated nephropathy. These data will encompass mortality, the frequency and severity of cardiovascular disease, progression of diabetic retinopathy,
Acknowledgements
We would like to thank Kim Hairston for her secretarial assistance. The past editor of this journal, Janet Wittes, PhD, was a member of the ESMC.
References (41)
- et al.
Prevention of glomerular basement membrane thickening by aminoguanidine in experimental diabetes mellitus
Metabolism
(1991) - et al.
Aminoguanidine decreases urinary albuminuria and high-molecular-weight proteins in diabetic rats
Life Sci
(1991) - et al.
Measurement of GFR utilizing a single subcutaneous injection of 125I-iothalamate
Kidney Int
(1973) - et al.
Properties of permuted-block design in clinical trials
Control Clin Trials
(1988) - et al.
Calcium channel blockers versus other antihypertensive therapies of progression on NIDDM associated nephropathy
Kidney Int
(1996) - et al.
Blood glucose control and diabetic complications
Ann Intern Med
(1986) Diabetic regulation and its relationship to microangiopathy
Metabolism
(1978)- et al.
Advanced glycosylation and the pathogenesis of diabetic complications
Ann Intern Med
(1984) - et al.
Advanced glycosylation end products in tissues and the biochemical basis of diabetic complications
N Engl J Med
(1988) Glycation of macromolecules
Advanced glycosylation end product in patients with diabetic nephropathy
N Engl J Med
Mechanistic studies of advanced glycosylation end product inhibition by aminoguanidine
Diabetes
Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat
Diabetes
Aminoguanidine ameliorates albuminuria in diabetic hypertensive rats
Diabetologia
Effects of nonenzymatic glycosylation of mesangial matrix on proliferation of mesangial cells
Diabetes
The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy
N Engl J Med
Prediction of creatinine clearance from serum creatinine
Nephron
Evaluation of sample size and power for analyses of survival with allowance for nonuniform patient entry, losses to follow-up, noncompliance, and stratification
Biometrics
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